Bioerodable implant composition comprising crosslinked biodegradable polyesters

ABSTRACT

An improved bone cement is comprised of a particulate biocompatible calcium phosphate ceramic and particulate resorbable calcium salt dispersed in a cross-linked biodegradable polyester matrix. The polymer/salt-particle composite exhibits good biomechanical strength/modulus characteristics with surgically acceptable cure times. When used for sustained release of biologically active agents in a physiological environment, controlled release of biological agents that are mixed into the composite can be achieved as the cement biodegrades. When used for bone/implant fixation, or as a filler or cement for bone repair, gradual biodegradation of the cement composite permits, under suitable circumstances, evantual replacement of the cement with developing bone tissue.

This is a division of application Ser. No. 07/024,973 filed Mar. 12,1987 now U.S. Pat. No. 4,843,112.

BACKGROUND AND SUMMARY OF THE INVENTION

This invention relates to an implantable bioerodable composition usefulfor the repair of living bone and for the administration of biologicallyactive substances. More particularly, this invention relates to amoldable, biocompatible, polyester/particulate composite that can beused for reinforcement of fractures and defects in bone, for fixation ofimplants and prostheses in bone, and for controlled-release delivery ofbiologically active agents.

Applicants have found that incorporation of biocompatible calciumphosphate ceramics and resorbable calcium salts into a cross-linkedbiodegradable polyester matrix produces a cement-like composition havingthe combined features of developing excellent biomechanical strengthwithin a short cure time and the capacity to degrade progressively, invivo, permitting, under suitable conditions, eventual replacement of thecement by body tissue. Thus, for example, where the present bioerodablecomposition is implanted in contact with bone for use to repair skeletaldeformities and injuries, to treat infections and diseases, or to "fix"prosthetic appliances in bone, the composition is gradually resorbed andmay then be replaced with living bone.

Surgical cements are well known in the art. Such cements are commonlyused for implant fixation in the surgical replacement of joint and bonetissue with prosthetic appliances. At the time of surgery the cement, ina fluid or semi-fluid pre-cured form, is injected or otherwise appliedbetween the bone and implant, flowing around the contours of the boneand implant and into the interstices of cancellous bone. Upon hardening(curing), the cement mechanically-interlocks the bone and implant.

Poly(methyl methacrylate) (PMMA) is the most widely used bone cement.PMMA cement comprises two components, a Powder of prepolymerized methylmethacrylate and a liquid monomer, methyl methacrylate, that are mixedat the time of surgery to form a paste-like cement material. PMMA cementis "permanent" in the sense that it is not degraded within the body.However, PMMA does not always provide "permanent" implant fixation.Loosening of prosthetic appliances due to cement failure has long beenrecognized as the single most prevalent problem in conventionalprosthetic arthroplasty, placing a serious limitation on the successfulduration of joint and bone replacement surgery. PMMA cement can sustainfatigue damage and has been known to crack and fail due to biomechanicaloverstressing. Yet another problem encountered with the current PMMAbone cement is that of the resorption of bony tissue immediatelyadjacent to the bone cement associated with the formation of abiologically active fibrous tissue membrane. Inducement of the formationof this membrane, which contains bone resorbing cells and enzymes, maybe a second mechanism, in addition to biomechanical overstressing,whereby PMMA cement loses its purchase in the surrounding bone andthereby fails to provide secure implant fixation.

More recent research efforts concerning fixation of bone prostheses havebeen directed to development of bone cements that are more compatiblewith bone tissue and to definition of implant surfaces capable ofreceiving direct bone ingrowth to enhance the bone-implant interlock.For example, prosthetic appliances have been constructed with a highlyporous coating on their bone-contacting surfaces, providing intersticesinto which bone tissue can grow to effect direct bone fixation of theimplant. For a bone to interlock with the porous surface structure ofthe implant, however, the implant must be firmly fixed at the time ofsurgery and load application must be minimized during the ingrowthperiod. This fixation method is, therefore, not entirely satisfactorybecause it is very difficult to provide adequate immobilization andstabilization of the implants during the bone ingrowth process. Furtherit is impossible to achieve bone ingrowth if a sufficiently large gapexists between the patient's bone and the porous implant surface.

One embodiment of the present invention relates to the use of across-linked biodegradable polyester/particulate composite for surgicalbone repair and implant fixation. The invention is based on thediscovery that particles of biocompatible sintered calcium phosphateceramics and more porous and resorbable calcium salts can beincorporated into a cross-linked biodegradable polymer matrix to producea surgical cement possessing physical and biological properties that aresuperior to conventional fixation cements. The polymer matrix is abiodegradable polyester solidified, or cured, immediately followingplacement in vivo by reaction with a chemical cross-linking agent. Thepolymer matrix serves as a supporting binder for particles ofbiocompatible inorganic salts and ceramics. The cured cement exhibitsexcellent biomechanical properties within short cure times. A patientreceiving an implant fixed using the present cross-linked polyestercomposite as a cement could be ambulatory early after surgery, therebyfacilitating rapid rehabilitation and minimizing costly hospitalization.

The polyester composite of this invention is formulated to allow aunique multi-stage process in which the cement is gradually resorbed andcould be replaced in vivo under suitable conditions by growing naturalbone. Thus an implant originally secured using the present cement could,with time, be secured by direct contact with living bone. Initially,particulate calcium salts in the cement are eluted from the polyestermatrix by body fluids creating small voids or cavities in the polymermatrix. Over time, the more slowly resorbable particulate ceramiccomponent is wholly or partially resorbed, and the polyester matrixitself degrades in vivo into its component non-toxic assimilabledicarboxylic acids, and dihydric or polyhydric alcohols. As the matrixof the cement slowly degrades voids are formed which can be filled in bynew bone. Eventually the extent of the new bone ingrowth could contactand secure the prosthetic appliance. The extent of new bone ingrowthwill vary depending upon local conditions affecting the implant. Forinstance, new bone ingrowth can be expected only if the bone cement isimplanted intraosseously as opposed to subcutaneously orintramuscularly. Furthermore, cancellous bone, with its greater bloodsupply, is more likely to facilitate bone ingrowth than cortical bone.The presence of an infecting organism would have an adverse affect oningrowth. Proportionally less ingrowth will occur with a large amount ofimplanted cement. Mixing host bone into the cement before use couldfacilitate bulk regrowth and new bone ingrowth.

In contrast to the situation mentioned above where a PMMA-fixedprosthesis can work loose with formation of surrounding fibrous tissue,living bone is able to heal and to remodel itself in response to stress;it is, therefore, resistant to the problem of failure with repeatedloading. This invention represents a significant improvement in boneimplant methodology.

It is known in the bone cement art to combine a bioresorbableparticulate compound such as tricalcium phosphate with anon-biodegradable polymeric resin. See, for example, U.S. Pat. No.4,373,217; U.K. Application No. 2,156,824; J. Vanio, Arch. Orthop.Traumat. Surg., 92, 169-174 (1978). However, such compositions do notfunction in vivo as does the cement of this invention. Because polymerresins of prior art composites are not biodegradable, prior artcomposite cements cannot be replaced by growing bone tissue.

The use of biodegradable polymers in vivo is also known in the art.Biodegradable polymers have been described for a variety ofapplications, including controlled release dosage forms andbioresorbable sutures. See U.S. Pat. Nos. 3,463,158; 4,080,969;3,997,512; 4,181,983; 4,481,353; and 4,452,973. Ibay et al. describe thepreparation and use of moldable implant appliances from vinylpyrrolidonecross-linked poly(propylene glycol fumarate) (PPF) for use as temporaryreplacements for soft tissue and/or bone following trauma. A. C. Ibay etal., Polymer Material Science and Engineering. 53, 505-509 (1985).Absorbable polyglycolic acid suture has been used successfully forinternal fixation of fractures. B. Roed-Peterson, Int. J. Oral. Surg.,3, pp. 133-136 (1974). There is nothing, however, to suggest use ofcross-linked biodegradable polymer composites for implant fixation. Noris there any suggestion to combine biodegradable cross-linkablepolyesters with biocompatible particulate calcium salts and ceramics toform the present particulate/polymer composites finding use as bonecements and as effective delivery systems for the sustained-release ofbiologically active substances.

It is therefore, an object of this invention to provide a biocompatibleresorbable surgical cement for repairing living bone.

It is another object of this invention to provide a method forpermitting bone ingrowth and bone adhesion to implanted prostheses.

Another object of this invention is to provide a biodegradableimplantable composite comprising a cross-linked biodegradable organicpolymer in combination with particulate, biocompatible calcium phosphateceramics and a resorbable calcium salts.

Still a further object of this invention is the use ofparticulate/cross-linked polyester composites as means forsustained-release delivery of drugs for treatment of disease inwarm-blooded vertebrates, and drug depot devices utilizing saidcomposites.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates compressive strength values measured in Megapascalsfor various weight compositions of PPF/MMA cement prepared in accordancewith this invention, implanted as 6×12 mm cylindrical specimenssubcutaneously in rabbits, and measured at time intervals ranging fromone day to three weeks after implantation.

FIG. 2 illustrates elastic moduli values measured in Megapascals forvarious weight compositions of PPF/MMA cement prepared in accordancewith this invention.

FIG. 3 is a graphic comparison of vancomycin levels in wound fluidfollowing implantation of PMMA and PPF matrices.

FIG. 4 is similar to FIG. 3 illustrating gentamicin levels.

FIG. 5 is similar to FIG. 3 illustrating vancomycin levels in serum.

FIG. 6 is similar to FIG. 3 illustrating gentamicin levels in serum.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a biodegradable cement compositionadapted for use in the surgical repair of living bone and for thecontrolled-release delivery of pharmaceutical agents. The compositioncomprises a particulate biocompatible calcium phosphate ceramic and aresorbable calcium salt dispersed in a cross-linked biodegradablepolyester matrix. The composition can be applied to bone-contactingsurfaces of prosthetic appliances (as a cement), or it can be insertedinto and around bone defects and cavities (as a filler), therebyproviding an effective means for treating or repairing living bone. Whena pharmaceutical agent is incorporated into the cross-linkedbiodegradable matrix it serves as a depot device for controlled-releaseof the pharmaceutical agent. Release of the agent occurs over aprolonged period of time upon implantation.

In general, the invention features a biodegradable polyester incombination with particulate calcium phosphate ceramics and resorbablecalcium salts. Polyesters useful in this invention are non-toxic,biodegradable, and bioresorbable, i.e., their degradation products areused by or are otherwise eliminated from the human body via existingbiochemical pathways. The polyesters should also be chemicallycross-linkable, i.e., possess functional groups which will allow thepolyester polymer chains to be reacted with cross-linking agentsreactive with said functional groups. Suitable polyester materialsinclude polyesters formed from biocompatible di- and tri-carboxylicacids or their ester-forming derivatives (e.g., acid chlorides oranhydrides) and di- or polyhydric C₂ -C₆ alcohols. The functional groupsin the polyester allowing for polyester cross-linking can derive fromeither the alcohol or the acid monomer components of the polyester.

Representative carboxylic acids for formation of polyesters useful inthis invention include Kreb's cycle intermediates such as citric,isocitric, cis-aconitic, alpha-ketoglutaric, succinic, malic,oxaloacetic and fumaric acid. Many of such carboxylic acids haveadditional functionalities which can allow cross-linking and thereforemeans for curing the present cement formulation from a paste-likemoldable mass to a hardened cement state. Fumaric acid is a preferredacid for forming the polyester of the present invention. It is adicarboxylic acid having a free-radical reactive double bond well suitedfor free radical induced cross-linking reactions.

Illustrative of C₂ -C₆ alkyl or aklylene alcohols useful to formpolyesters in accordance with this invention are ethylene glycol,2-buten-1,4-diol, 2-methyl-2-buten-1,4-diol, 1,3-propylene glycol,1,2-propylene glycol, glycerine, 1,3-butanediol, 1,2-butanediol,4-methyl-1,2-butanediol, 2-methyl-1,3-propanediol,4-methyl-1,2-pentanediol, cyclohexen-3,4-diol and the like. In apreferred embodiment, the polyester component of the present compositecement is poly(propylene glycol fumarate)(PPF) formed by thecondensation (esterification) reaction of propylene glycol and fumaricacid.

PPF is advantageous in the present invention because PPF possesses twochemical properties that are critical to the function of a biodegradablebone cement. The first is the ease by which PPF can be degraded in vivointo its original fumaric acid and propylene glycol subunits. Bothfumaric acid and propylene glycol are non-toxic and well-tolerated invivo. As a Kreb's cycle intermediate, fumaric acid plays an essentialrole in the process by which food is converted into energy. Propyleneglycol is used throughout the food industry as a food additive and canbe metabolized or excreted by the body. The second critical property isthat each subunit of the PPF prepolymer contains an activatedunsaturated site through which the polyester can be cross-linked withvarious olefinic free-radical induced cross-linking agents.

The polyester is cross-linked during the curing period for the p resentcomposite cement to form a solidified cement matrix. Where the reactivechemically functional groups in the polyester are carbon-carbon doublebonds (e.g., in the preferred PPF polyester component) representativecross-linking agents are methyl methacrylate (MMA), N-vinylpyrrolidone,and like olefinic cross-linking agents. A preferred cross-linking agentis MMA, which exists as a clear liquid at room temperature. It isparticularly suitable for free radical induced cross-linking of PPF inaccordance with a preferred embodiment of this invention.

The preparation of the present composite cement typically involvescombining the polyester and the cross-linking agent into a substantiallyhomogeneous mixture, and adding the particulate calcium phosphateceramic and calcium salt to form a moldable composite cement mass whichhardens on curing, i.e., completion of the cross-linking reaction. Thenumber average molecular weight [M(n)] and molecular weight distribution[MWD] of the polyester should be such that the polyester andcross-linking agent can be combined to form a substantially homogenousmixture. Preferably the cross-linking agent is a liquid and thepolyester is substantially soluble in, or miscible with, thecross-linking agent. Alternatively, the cross-linking agent can be asolid soluble in a liquid low molecular weight polyester, or a liquidmiscible therewith. Under ideal circumstances, the cross-linkingreaction will result in a homogenous (uniformly cross-linked)polyester/particulate composite cement.

In a preferred embodiment poly(propylene glycol fumarate)(PPF) iscombined with an amount of methyl methacrylate sufficient upon reactioninitiation, to cross-link the polyester to the level necessary to form arigid cross-linked PPF polymer matrix for the admixed particulatecalcium salts. Preferred MWD for the PPF ranges from about 500 to about1200 M(n) and from about 1500 to about 4200 M(w).

In a preferred embodiment of this invention, the liquid polymer phase ofthe cement formulation is about 80 to about 95 percent by weight PPF andabout 5 to about 20 percent by weight MMA monomer. The optimal weightpercentages for mechanical strength are approximately 85 percent PPF andabout 15 percent MMA. The MMA monomer is typically stabilized to preventpremature polymerization, i.e., prior to mixing with PPF, with a fewparts per million of hydroquinone.

It is important that the proportions of PPF and MMA are controlled. Iftoo much MMA monomer is added, the MMA molecules can Polymerizethemselves without being interrupted by the PPF chains. The result is amaterial that behaves like conventional PMMA bone cement and does notbiodegrade. If too little MMA monomer is added, the PPF polymer chainswill not be effectively cross-linked and the cement will not cure toform a matrix of sufficient rigidity.

The MMA-PPF cross-linking reaction proceeds via a free-radicalpropagated polymerization reaction. The cross-linking reaction thereforeis, in practice, accelerated by addition of a free-radical initiator.One suitable free-radical initiator for this process is benzoylperoxide.

A catalytic amount (less than 1% by weight) of dimethyltoluidene (DMT)is typically added to accelerate the formation of free radicals at roomtemperature. Thus, the rate of cross-linking (i.e. time for curing orhardening of the cement) can be adjusted by controlling the amount ofDMT added to the PPF/MMA mixture. The cement-curing rate can be adjustedso that the cement is substantially cured in a period ranging from lessthan a minute to over 24 hours. The preferred curing time depends, ofcourse, upon what is the most practical period of time for surgicalpurposes. The curing period should be sufficiently long to allow thesurgeon time to work with the cement to mold it or apply it to theappropriate surfaces. At the same time, the cure rate should be highenough to effect, for example, implant stabilization within a short timefollowing the surgical procedure. The polymerization or solidificationperiod for bone implant fixation typically ranges from about 5 to about20 minutes, and preferably about 10 minutes.

The particulate phase of the present cement is comprised ofbiocompatible particulate calcium phosphate ceramics and particulatebioresorbable calcium salts. The particulate phase initially acts as astrength-imparting filler, much like the aggregate component ofconcrete. However, in vivo, the calcium salt particles are slowly elutedfrom the cement matrix by body fluids, leaving sites for bone ingrowthinto the polymer matrix. Exemplary resorbable calcium salts effective inthe composition of this invention include calcium sulfate, calciumsulfate hemihydrate (plaster of Paris), calcium carbonate, calciumhydrogen phosphate, certain porous precipitated forms of calciumphosphate and the like.

Biocompatible calcium phosphate ceramics are selected particularly inthe bone repair embodiment of this invention for their known propertiesvis a vis growing/living bone; that is, they are known to promoteinterfacial osteoconduction. Osteoconduction refers to the ability of asubstance to induce bone to grow on it. As used herein the term "calciumphosphate ceramics" is to be distinguished from the second particulatecomponent "bioresorbable calcium salts", and refers to a number ofsintered (heat-consolidated) materials approximately defined by theformula Ca₃ (PO₄)₂ including not only tricalcium phosphate itself butalso apatites, such as hydroxyapatite, and phosporites. The particulatecalcium phosphate ceramics used in accordance with this invention arecharacterized themselves as "resorbable" but they are resorbable at amuch lower rate than the more porous particulate "calcium salts"component of the present composites. Calcium phosphate ceramics are ingeneral prepared by sintering more soluble calcium salts, for example,Ca(OH)₂, CaCO₃ and CaHPO₄ with P₂ O₅ or with each other. Calciumphosphate ceramics and their use in implant materials are known in theart. See, for example, U.S. Pat. Nos. 3,787,900; 4,195,366; 4,322,398;4,373,217 and 4,330,514.

Bone particles, either autograft or allograft, can also be included inthe particulate phase. Including natural bone in the cement enhances theproperty of osteoinduction or the ability to induce new bone formation.

In a preferred embodiment of this invention, a mixture of calcium saltsand calcium phosphate ceramics is used to form the particulate phase. Acoarse tricalcium phosphate ceramic having a porous surface and aparticle diameter of about 300 to about 600 microns is mixed withfine-particulate or powdered calcium carbonate or plaster of paris(calcium sulfate hemihydrate) having a maximum particle size of lessthan about 10 microns and preferably less than about 5 microns indiameter. Use of smaller diameter tricalcium phosphate particulatelowers the mechanical strength of the cement but increases its abilityto penetrate into small interstices. The particulate tricalciumphosphate is preferably combined with the calcium carbonate or calciumsulfate in ratios ranging from about 1:4 to about 4:1 by weight, andpreferably in a ratio of about 1:1 to form the particulate component ofthe present biodegradable polymer composites.

In the cement composition of this invention, the weight ratio of calciumsalts and calcium phosphate ceramics (the particulate phase) to thepolyester matrix phase (polyester plus cross-linking agent) can rangefrom about 5:1 to about 1:2. Preferably, the cement composition isprepared by mixing about 2 parts by weight of particulate Phase withabout 1 part by weight polymer matrix phase. The ratio of particulatephase to polymer phase can be adjusted to provide the functionalcharacteristics warranted by any given surgical application of thecomposite cement.

A kit for preparing the particulate cross-linked polyester composite ofthis invention can be conveniently packaged for surgical applications.For example, the inorganic particulate calcium salts, calcium phosphateceramics, and benzoyl peroxide can be packaged as a particulate powderphase while the PPF and MMA can be packaged as a liquid phase.

In the operating room, the surgeon mixes the powder and liquid (polymerplus cross-linker) phases to form a paste-like mass. In a preferredcomposition, the resulting surgical cement is comprised of approximatelyone third by weight of the liquid phase and approximately two thirds byweight of the particulate phase. At this time, the surgeon may wish toadd to the cement mixture bone that is taken from the patient and groundinto particulate form in order to enhance osteoinduction or the abilityto induce new bone formation to the cement. The cross-linking/curingprocess begins immediately at room temperature when the DMT is added.Alternatively all ingredients can be mixed together except for thebenzoyl peroxide which is added when initiation of the curing process isdesired. The cross-linking reaction can transform the bone cement froman injectable or moldable paste into a durable solid particulatecomposite within about 10 minutes.

Although cement solidification can proceed sufficiently within a 10minute period to form a solid material, the reaction continues toproceed at a slower rate for a period of several hours to several days.

The particulate calcium salts and organic polymers employed in thecomposition of the present invention are available commercially or arereadily prepared through procedures which are known in the art.

The present particulate/polymer composites have been found to provide anexcellent matrix for the sustained release in vivo of biologicallyactive substances incorporated into the composite prior to or during thecross-linking (curing) step for preparing the present composites. Thus adrug substance/Pharmaceutical agent incorporated into thepre-crosslinked polymer/particulate mixture to form about 0.1 to about33% by weight, more preferably about 2% to about 5% by weight, of thedrug-composite mixture will be released in vivo (upon implantation ofthe cured composite) over a period ranging from about two days to about30 days and longer depending on the nature of the composite formulation.

Release rate from a delivery system based on the present composites is afunction of the degree of cross-linking, the nature and concentration ofthe drug substance in the matrix, particulate size/solubility,nature/biodegradability of polyester component and the "in vivoenvironment" of the implanted composite. Thus use of the presentcomposites as a drug delivery system allows for a significant degree ofcontrol over drug release.

The cross-linking reaction employed to "cure" the present composites isonly mildly exothermic compared to, for example, PMMA polymerization.This allows for formulation of sustained release delivery systems formore thermally labile drugs.

The drug delivery systems in accordance with this invention can beformulated and implanted, or injected, either before or after curing(the cross-linking reaction) is complete. The drug/cross-linkedpolymer/particulate composites are typically implanted surgically at asite in the body where high drug concentrations are desired. Thus, forexample, in the treatment of osteomyelitis, antibiotic-containingcomposites can be molded to conform to naturally occurring bone defectsor they can be inserted into cavities formed by the surgeon specificallyfor receiving the composition. Similarly, the composites can beimplanted or injected into soft tissue for sustained drug release. Animportant advantage of the present composite delivery systems is that asecond surgical procedure to remove the "spent" drug delivery device isnot required. The device is with time degraded and its degradationproducts are absorbed by the body.

The present invention is further illustrated by the following examples,none of which are to be construed as limiting the invention in anyrespect:

EXAMPLE 1

A poly(propylene glycol fumarate) (PPF) based particulate compositesurgical cement was prepared as follows: 3.0 moles of fumaric acid (348grams) and 3.3 moles of propylene glycol (251 grams) were placed in atriple-necked 1000 cc flask with overhead mechanical stirrer,thermometer, and Barret trap beneath a condenser. The reaction wasinitiated by heating at 145 C with continuous stirring. After about 2hours, water began to collect in the Barret trap. The mixture was heatedfor 5 hours by which time about 40 ml of water had been collected. Thetemperature was then increased to 180° C. in order to drive off thepropylene glycol. The progress of the reaction was monitored by removingsamples and measuring their viscosity at 100° C. The viscosity initiallymeasured about 2 poise at 100° C. and gradually rose to 15 poise, atwhich time the reaction was terminated. Terminating the polymerizationat the proper time is critical. The proper endpoint occurs when the PPFreaches a viscosity of about 10 to about 15 poise measured at 100° C.This yields PPF with a number average molecular weight of about 500 toabout 1000, preferred for use in accordance with this invention.

The mixture was cooled to room temperature to prevent furtherpolymerization. In order to remove the excess fumaric acid precipitate,85 parts by weight of the mixture were diluted with 15 parts by weightmethylmethacrylate (MMA) monomer, placed on a rotary stirring rack for12 hours at 37 C to assure thorough mixing, and centrifuged at 6000 RPMfor 30 minutes. The PPF polymer formed the supernatant.

Six grams of the liquid 85% PPF/15% MMA mixture were mixed with thefollowing particulate components: 0.4 grams of benzoyl peroxide powder,7.5 grams of particulate tricalcium phosphate (30-45 mesh), and 7.5grams of powdered calcium carbonate. These ingredients were warmed to40°-50° C. to facilitate the mixing process. This mixture exhibited nosigns of solidifying. At time of use, 2 drops of dimethyl-p-toluidine(DMT) was added and thoroughly mixed. The resulting cement wasimmediately molded into specimens and allowed to cure at 37 C and 100%relative humidity. The fresh cement was also implanted into experimentalanimals. Approximately 5 minutes working time was available before thecement began to harden. Unconfined mechanical testing of the curedmolded specimens, according to ASTM standards for acrylic cements, gavea compressive strength of 19 MPa and an elastic modulus of 200 MPa.

EXAMPLE 2

In vitro tests of biodegradable cement materials prepared in accordancewith Example 1 were conducted in various liquids. PPF/MMA specimens wereplaced in water buffered at neutral pH. Initially, the water causedslight swelling of the matrix and the specimens decreased in mechanicalstrength and stiffness. After a few days, with the onset of thesecondary calcium ion reactions, the specimens returned to theiroriginal material Properties. No evidence of degradation occurred.

Samples were also placed in an alkaline solution of pH 10. The specimenslost strength quickly because of the swelling of the polymer. Because ofthe polymer degradation due to the high pH, the samples did not regainstrength. Within a few days, the specimens could be easily crushed withthe end of a pencil.

These results were obtained for PPF/MMA specimens prepared having aweight ratio of PPF to MMA of about 85:15. When higher amounts of MMAwere used, e.g., 30 weight percent, degradation of the PPF/MMA specimensdid not occur. The specimens regained their material properties andmaintained them indefinitely.

When the specimens were placed in an acidic solution, the plaster ofParis was quickly leached out of the specimens. The specimens lost theirstiffness but retained their shape due to the strength of the polymer.

These in vitro results demonstrated that the PPF/MMA bone cementpossessed appropriate mechanical properties and chemical properties foruse as a biodegradable cement for orthopedic applications.

EXAMPLE 3

Additional experiments were conducted to evaluate the mechanicalproperties of the PPF/MMA cement in animal implantation applications.Specimens were prepared in accordance with the Procedures set forth inExample 1.

Three groups of standard 6×12 mm cylindrical specimens were implantedsubcutaneously into a rabbit's back. At least six (6) rabbits weresacrificed for mechanical testing of implanted specimens at intervals ofone day to three weeks. Results of the biomechanical evaluation are setforth in FIGS. 1 and 2. The compressive strengths of the PPF cementimplant measured at one day, four days, one week, and three weeks areset forth in FIG. 1. FIG. 2 depicts the elastic moduli values measuredat the same intervals.

Four different compositions of cement were tested in each rabbit.Crosslinked PPF specimens cross-linked with 10%, 15%, 20%, and 30% MMAexhibited proportionately increasing mechanical strength and modulusvalues. The one-day values for material properties for allconcentrations were approximately one-half that of the controls. This isbelieved to have been caused by swelling of the polymer in a wetenvironment. By four days, all specimens had significantly increasedtheir material properties. The 15% MMA specimens exhibited compressivestrength of 10 MPa. This is believed to be due to the secondary calciumion effect.

At one, two, and three week intervals, differences in materialproperties were observed, depending upon the MMA concentration. For 20%and 30% MMA specimens, only a slight drop in mechanical strength wasnoted. This is believed to have been due to the leaching out of theplaster of Paris. For the 10% and 15% MMA specimens, a more significantdrop in mechanical strength was noted. This is believed to have been duenot only to the plaster of Paris leaching out but also to the initialstages of polymer degradation. Subsequent experiments using 15/85MMA/PPF cement showed that, after seven weeks of subcutaneousimplantation, the compression strength of specimens had fallen below 1.0MPa and many had crumbled and fragmented.

EXAMPLE 4

In vitro implantation of the biodegradable cement materials, prepared inaccordance with Example 1, were conducted to test their effectiveness ascarriers for sustained release of antibiotics. Prior to the addition ofDMT, either gentamicin or vancomycin were mixed into the cement at aratio of 1 gram of antibiotic to 30 grams of cement. The cement was thenactivated with DMT and molded into 6×12 mm cylindrical specimens asdescribed above. Similar specimens were prepared with conventional PMMAcement loaded with antibiotics in the same manner. All specimens wereimplanted subcutaneously in rats. Wound fluids aspirated from around theimplants and blood samples were measured for concentrations ofantibiotics by immunoassay from 1 to 14 days post-operatively as shownin FIGS. 3, 4, 5, and 6. The PPF/MMA cement produced significantlyhigher local antibiotic levels in the wound fluid for both gentamicinand vancomycin, for a longer duration than did PMMA. Bloodconcentrations of both antibiotics remained well below toxicconcentrations for both cements.

EXAMPLE 5

Treatment of Experimental Osteomyelitis in a Rat Model:

Seven Sprague-Dawley retired male breeder albino rats were divided into4 groups as noted below. All rats underwent sterile surgical proceduresunder sodium pentobarbitol general anesthesia. Three successive surgicalprocedures were performed on each rat.

The first procedure was identical for all rats. The flat surface of theanteromedial tibial metaphysis was surgically exposed via a 1.5 cmlinear incision just distal to the knee joint and 2 mm medial to theanterior tibial crest. The periosteum was split and gently moved asideusing a periosteal elevator. Using a high speed drill, (Hall Air SurgeryInstruments micro drill, 5053-01, Zimmer, U.S.A) and a 2 mm burr bit, ahole was made through the anteromedial metaphyseal cortex andunderlying. Care was taken not to violate the far cortex while drilling.Immediately following drilling, a suspension of S. aureus (1.0×10⁶ CFU/1ul) was prepared using the Prompt Inoculation System (3M, No. 6306). Tenul were injected into the wound site. This represented an inoculum ofapproximately 1.0×10⁶ CFU. Care was taken to deliver all of the inoculumto the drill hole and avoid overflow. Immediately following inoculation,a 2×3 mm performed PMMA cylinder with a central 4 mm wire (to aidradiographic detection and facilitate later removal) was placed as aforeign body in the burr hole over the inoculum. A synthetic resorbablesuture (6.0 VICRYL suture, Ethicon, Inc.) was used to Partially closethe periosteum over the drill hole to secure the implant. The distal 2/3of the skin incision was then closed using 4.0 VICRYL, leaving theproximal 1/3 of the incision open as a potential site for drainage. Only3 interrupted sutures were used. Postoperative lateral radiographs wereobtained of all rat tibiae. Rats were then returned to cage activity for3 weeks.

At 3 weeks, all rats except one (LONG) had their implants removedsurgically using sterile technique. The appearance of the infection sitewas recorded. The LONG rat was left at cage activity with his originalimplant for the duration of the experiment. Implants were inoculated onblood agar plates and into thioglycollate broth and incubated for 24hours at 35° C. in 5% C)₂. Subcultures of the broth were made asnecessary to identify all infecting organisms. A sterile gauze 4×4 wasused to manually wipe away pus from the drill hole and surrounding softtissue of the left hindlimb but no formal debridement was performed. Theright hindlimb underwent formula debridement of infected and necroticbone and soft tissue bone and soft tissue and the original drill holewas reamed to 4 mm and the edges undermined using the Hlal micro airdrill and 2 mm burr. Two animals were treated bilaterally withgentamicin and vancomycin and PPF/MMA packed into, and allowed topolymerize in the drill hole osteomyelitic site. Two animals weretreated similarly but with gentamicin and vancomycin in PMMA. Gentamicinand vancomycin were added at a ratio of 2 gm to 60 gm of either PPF/MMAor PMMA to prepare treatment samples.

Antibiotic impregnated PPF/MMA specimens were prepared in the followingmanner: PPF 96 gm, of as yet unpurified fumaric acid) and MMA (1 gm)were thoroughly mixed at 37 degrees C. until the PPF was completelydissolved in the MMA. The resultant matrix material (85% PPF and 15%MMA) was centrifuged at 6000 rpm for 45 minutes to remove the suspendedfumaric acid. The `purified` PPF/MMA matric was then mixed with benzoylperoxide (0.25 gm, a crosslinking catalyst) and the particulate phasewhich consisted of TCP (7.5 gm, 30-45 mesh, 355-600 micron diameter) andmedical grade calcium carbonate powder (7.5 gm.). After thorough mixingof the particulate composite, gentamicin sulfate powder (Sigma ChemicalCo.) or vancomycin hydrochloride lypholized powder (Lederle ParenteralsInc.) was added and mixed well. Finally, dimethyl-p-toluidine (DMT)(2drops) was added to initiate cross-linkage of the cement. (A 22.25gm·batch of the particulate composite was prepared and 15 gms of thiswas mixed with 0.5 gm of antibiotic to give a 2 gm/60 gm ratio or 3.3%antibiotic. Two control animals had their initial foreign body implantsremoved and were not treated. All wounds were closed loosely using 2 to3 interrupted 4.0 VICRYL sutures in the distal 2/3 of the wound only.Again the proximal 1/3 of each wound was left open. Pre andpostoperative radiographs were obtained to document osteomyeliticchanges.

Three weeks later (6 weeks post infection) all animals were sacrificedby intraperitoneal sodium pentobarbitol followed with an intracardiacinjection of sodium pentobarbitol. In the operating room under sterileconditions, the hindlimbs were dismembered and partially surfacesterilized by immersion in 95% alcohol followed by spraying withpovidine-iodine solution which was allowed to air dry. Using a new setof sterile instruments the tibial infection site was exposed and itsappearance recorded. The cement plugs and adjacent bone were thenexamined bacteriologically. Standardized 4 mm thick `wafer-shaped` tibiasegments, which included, the infection site and cement-antibiotic plug,were cultured quantitatively. Bone segments were inoculated into 2 ml oftrypticase soy broth (TSB). The mixture was vortexed, and serial 10-folddiulations in TSB were made. A 10 ul inoculum was subcultured to 5%sheep blood agar plates that were incubated for 24 hours at 35° in 5%Co₂. Colonies were counted on plates with approximately 30-100 coloniesonly.

Results: Three weeks post administration of the S. aureus inoculum allanimals demonstrated clinical and radiographic signs consistent withestablished chronic osteomyelitis. These included abscesses, drainingsinuses, radiographic osteolysis and sequestration, periosteal new boneformation and pathologic fractures. Six weeks following infection, i.e.,following three weeks of treatment or control protocols, all controlanimals demonstrated clinical signs of infection whereas both treatedgroups appeared more normal clinically. Radiographs were essentiallyunchanged. All tibia sites from all animals grew mixed bacterial floraincluding S. aureus, consistent with chronic osteomyelitis. In all casesthere were dramatic differences between treated animals (PPF/MMA andPMMA with antibiotics) and control animals. In one PPF/MMA treated case,there was complete sterilization of the infected site. In all cases,where debridement was performed, there was at least 2 to 3 orders ofmagnitude fewer organisms cultured from PPF/MMA animals than from PMMAtreated animals. Control animals demonstrated 1 to 6 orders of magnitudemore bacteria by quantitative culture than did treated animals.

While the composition of the present invention has been described foruse as a medication-bearing composition for the controlled delivery ofmedication in vivo as well as for use as a surgical cement forprosthetic appliances, such descriptions are illustrative only and arenot intended to be limiting in any way. There are many otherapplications for the biodegradable composites of the present invention.For example, the surgical cement of the present invention could be usedfor the repair of osteoporotic fractures. Such fractures are difficultand often not possible to treat by conventional internal fixationmethods using bone plates and screws because the bone screws are proneto loosen or to cut through the weaker osteoporotic bone. Although somesurgeons use conventional PMMA bone cement to secure the bone screws,there is a risk that PMMA will actually impair the healing process. Anysuch impairment is detrimental because if the bone fragments do notheal, the fixation eventually will fail.

Moreover, osteoporosis-induced fractures frequently involve acrushing-type injury by which porous bone collapses into itselftypically causing a large void or bony defect at the site of thefracture. In order to achieve secure stabilization of the fracture, thisbony defect must be filled in. Conventional surgical techniques employthe use of a bone graft from another site in the body to pack and fillthe cavity. The bone graft consolidates as living bone slowly grows intothe graft. Patients with such fractures in the lower extremities mustremain non-weight-bearing for periods of up to three months because thebone grafts are too weak to provide sufficient structural support.Hospitalization, nursing home care, traction, and medical complicationsassociated with immobilization are, of course, very expensive andproblematic for the patient. The use of a biodegradable bone cementwould alleviate the problems caused by prolonged, non-weight-bearingimmobilization. A bone cavity could simply be filled with thebiodegradable cement of the present invention, which would quicklyset-up to form a strong solid mass. Patients could begin fullweight-bearing activities within several days after the operation. Theadvantages are obvious in that the patient would experience a muchshorter hospitalization period. Over time, the biodegradable bone cementwould slowly resorb as the fracture healed and the cement could bereplaced by living bone.

In addition, the surgical cement of the present invention can also beemployed advantageously in the treatment of bone tumors. Such treatmenttypically involves excision of the tumor as well as portions of thesurrounding bone, leaving a large cavity in the bone. An autogenous bonegraft, or bone harvested from another site in the patient's body, is theconventional and accepted technique for filling such bony defects. Whileexperimental clinical tests show that autogenous bone provides the mostrapid incorporation of new bony ingrowth into a bone cavity, adisadvantage is that associated with the morbidity caused by therequired surgical exposure for harvesting of the patient's bone.Moreover, some patients, particularly osteoporotic individuals, havevery limited amounts of bone that are appropriate for use as a graft.Alternatively, allographs, i.e., bones taken from other individuals, maybe used as bone-grafting material. There are certain risks associatedwith such allographs, however, including the transfer of infections andeven unrecognized malignant cells from the harvested patient to thegrafted patient as well as the problem of immunologic barriers betweenall individuals. Furthermore, such processes are complicated andlabor-intensive.

For these reasons, some surgeons have begun to employ synthetic bonesubstitutes. The two most common types of substitutes arehydroxyappatite (HA) and tricalcium phosphate (TCP). HA and TCP havebioactive surfaces that promote osteoconduction when implanted in a bonecavity. In addition, TCP has the property of being slowly resorbed bythe host tissues. A biodegradable surgical cement would have importantadvantages over conventional bone substitutes such as TCP and HAParticulates because the cement could be injected and molded to fill acavity of any shape and would harden sufficiently to immediately allowweight-bearing activities. Moreover, unlike man-made materials, theproblems with procurement, infection, and storage would be obviated.

While we have described the invention with respect to specificmaterials, operating conditions, and procedures, such are illustrativeonly. Numerous modifications and equivalents will be apparent to thoseof ordinary skill in this art without departing from the spirit of theinvention.

What is claimed is:
 1. A composition comprising a particulatebiocompatible resorbable calcium salt, a sintered particulate calciumphosphate ceramic and a biologically active agent dispersed in a polymermatrix formed by cross-linking a biodegradable polyester of adicarboxylic acid comprising fumaric acid and a polyhydric C₂ -C₆alcohol with about 5 to about 20% by weight of methyl methacrylate, saidpolyester having a number average molecular weight of about 500 to about1200.
 2. The composition of claim 1 wherein said biologically activeagent forms about 0.1 to about 33 percent by weight of the matrix.
 3. Amethod of repairing living bone which method comprises applying to saidliving bone a biodegradable bone cement for fixation of bone or jointprostheses, said bone cement comprising a polymer matrix formed bycross-linking a biodegradable polyester of a dicarboxylic acidcomprising fumaric acid with about 5 to about 20% by weight of methylmethacrylate, said polyester having a number average molecular weight ofabout 500 to about
 1200. 4. The method of claim 3 wherein thebiodegradable bone cement comprises methyl methacrylate cross-linkedpoly(propylene glycol fumarate), a calcium phosphate ceramic and abiocompatible resorbable calcium salt and wherein the weight ratio ofthe cross-linked polymer to ceramic plus salt is about 2:1 to about 1:5,respectively.
 5. In the method of surgical repair of a bone or jointcomprising use of a polymeric cement in contact with living bone, theimprovement consisting essentially of preparing the polymeric cementbyforming a dispersion of a particulate biocompatible calcium phosphateceramic and a particulate biocompatible resorbable calcium salt in amixture of a polymer matrix-forming fluid comprising a (1) a chemicallycross-linkable biodegradable polyester of a dicarboxylic acid comprisingfumaric acid having a number average molecular weight of about 500 toabout 1200 and (2) about 5 to about 20% by weight methyl methacrylate asa cross-linking agent, and initiating a chemical reaction between thepolyester and the cross-linking agent prior to using said cement incontact with living bone.
 6. The improvement of claim 5 wherein thebiodegradable polyester is poly(propylene glycol fumarate).
 7. Animplantable article for use in the sustained release of effectiveamounts of a biologically active agent into a physiological environment,said delivery system comprising a biologically active agent dispersed ina polymer matrix formed by cross-linking a biodegradable polyester of adicarboxylic acid comprising fumaric acid and a polyhydric C₂ -C₆alcohol with about 5 to about 20% by weight methyl methacrylate, saidpolyester having a number average molecular weight of about 500 to about1200.
 8. The article of claim 7 wherein the biologically active agent isan antibiotic.
 9. A bioerodable polymer matrix composition comprising abiodegradable polyester of a dicarboxylic acid comprising fumaric acidand a polyhydric C₂ -C₆ alcohol cross-linked with about 5 to about 20%by weight of methyl methacrylate, said biodegradable polyester having anumber average molecular weight of about 500 to about
 1200. 10. Thebioerodable composition of claim 9 wherein the C₂ -C₆ alcohol ispropylene glycol.
 11. The composition of claim 1 wherein thebiodegradable polyester is a polyester of fumaric acid and propyleneglycol.